In spite of a plethora of published studies in laboratory animals that have documented effects of cocaine on specific central nervous system neurotransmitter systems, there is remarkably little known about the chronic effects of this psychostimulant on the human brain. In this proposal we seek to scrutinize the effects of chronic cocaine abuse in humans by assessment of neurochemical alteration in approximately 50 brain regions derived from post-mortem brain tissue of confirmed cocaine abusers (with segmental hair analysis to document the temporal pattern of cocaine use) and age- and sex-matched controls. Through cocaine's actions on monoamine transporters, the preclinical literature has clearly implicated dopamine (DA), serotonin (5MT) and norepinephrine (NE)-containing neurons in mediating the actions of cocaine; there is also considerable evidence implicating two neuropeptide neuronal systems (corticotropin-releasing factor [CRF] and neurotensin [NT]) in the actions of this drug of abuse. Alterations in the monoamine transporters will be assessed by measurement of: radioligand binding, transporter protein concentration by the use of newly developed specific antibodies to the transporters, and mRNA expression of the transporters. Alterations in CRF and NT systems will be assessed by measurement of the neuropeptides, neuropeptide mRNA expression, neuropeptide receptor binding, neuropeptide receptor mRNA expression, and in the case of the CRF system, the CRF-binding protein and CRF signal transduction. These studies will provide novel data on the effects of cocaine abuse on specific neurotransmitter systems in the human central nervous system.